Contents Physiology and pathophysiology of type 2 diabetes 5/15/2018 3:51 PM Contents Physiology and pathophysiology of type 2 diabetes Role of Incretins, DPPIV inhibitors, SGLT 2, inhibitors, How intensely should we treat and are there problems Contents Now we will discuss the role of incretins.

Treatment of Type 2 Diabetes Go For Goal!! The Earlier the Better

So What is the Window of Opportunity

Published Conceptual Approach Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal Published Conceptual Approach OAD + multiple daily insulin injections Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD + basal insulin 10 9 A1C Goal 8 Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal The yellow line depicts a conceptual view of a conventional stepwise treatment approach. Hypothetically, patients treated with this approach would have a considerable glycemic burden (time spent above A1C goals).1 The orange line depicts a conceptual view of an aggressive A1C goal-oriented approach that would initiate changes in therapy earlier (within several months of goals not met).1 Hypothetically, patients treated with this approach might be able to attain such A1C results as those depicted by the straight orange line. This approach also calls for earlier use of combination therapy in appropriate patients.1 7 Purpose To show conceptually that early, aggressive intervention may reduce the glycemic burden of type 2 diabetes. Takeaway A treat-to-goal therapeutic approach should include aggressive treatment whenever A1C is above goal. The overall glycemic burden can be reduced with this approach. 6 Mean A1C of patients Duration of Diabetes Conventional stepwise treatment approach Earlier and more aggressive intervention approach OAD=oral antidiabetic agent. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Permission pending. 4 Reference 1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B; on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59(11):1345–1355.

The Paradigm Shift in the Management of Type 2 Diabetes Patient Age Disease Duration 40 45 50 55 60 65 70 75 5 10 15 20 Other Comorbidities None Few/Mild Multiple/Severe Hypoglycemia Risk Low High Moderate Least Intensive 8.0% Most Intensive 6.0% Less Intensive 7.0% Established Vascular Complications Early Microvascular Advanced Microvascular Psychosocioeconomic Considerations Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, Comprehensive Support Systems Less Motivated, Nonadherent, Limited Insight, Poor Self-Care Capacities, Weak Support Systems CV 6/14 Ismail-Beigi F et al: Ann Intern Med 154:554-559; 2011 and Inzucchi SE et al: Diabetes Care 35:1364-1379; 2012

Mr. and Mrs. Smith What is your target A1C? 79 year old male with CAD s/p CABG in 2002, DM II (dx over 20 years), BPH, HTN, and OA He is independent in his ADLs but his daughter helps with groceries and cleaning. “Doting husband” who helps to take care of his wife with Alzheimer’s. He is seeing you in clinic for medical management. What is your target A1C?

What is your Target A1c for Mr Smith? Please select one of the following: A. 6.5 B. 7.0 C. 7.5 D. 8.0 E. 8.5

Kendall DM, Bergenstal RM. © International Diabetes Center 2009 Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS   DCCT / EDIC* ACCORD  ADVANCE VADT Overview of the microvascular, macrovascular and mortality outcomes from large T2DM and T1DM randomized clinical trials that focused on the relationship between glycemic control and complications. Initial Trial Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Long Term Follow-up * in T1DM

Can we apply data to Mr. Smith? RCT – tight glycemic control Mean age Initial HgbA1C Intensive vs. conventional Duration of DM UKPDS 33 UK Prospective Diabetes Study (1998) 53 7.09 vs. 7.05 “Newly” dx UKPDS 34 7.1 vs. 7.2/7.3 ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (NEJM 2008) 66 7.5 vs. 7.5 8 years Mean ACCORD Action to Control Cardiovascular Risk in Diabetes (NEJM 2008) 62.2 8.3 vs. 8.3 10 years Median STENO-2 (NEJM 2008) 55 8.4 vs. 8.8 Not reported VADT Veterans Affairs Diabetes Trial (NEJM 2009) 60 9.4 vs. 9.4 11.5 years

Can we apply data to Mr. Smith? RCT – tight glycemic control Achieved HgbA1c (Intensive vs. conventional) Benefit/Risk Time to derive benefit UKPDS 33 7.0 vs. 7.9 ↓ microvascular endpoint *retinal photocoagulation 10 years UKPDS 34 7.4 vs. 8.0 Median ↓ all cause mortality, MI, and “any DM related endpoint” *metformin 10.7 years ADVANCE 6.5 vs. 7.3 Mean ↓ in new onset microalbuminuria ↓ in nephropathy 5 years ACCORD 6.4 vs. 7.5 ↓ in non-fatal MI ↑ All cause and CV mortality 3.5 years, stop STENO-2 7.9 vs. 9 7.7 vs. 8 ↓ in all cause mortality ↓ in CV mortality* 8 years, 5.5 years VADT 6.9 vs. 8.4 ↓ progression of albuminuria 5.6 years

Benefit vs. Risk for Mr. Smith? UKPDS ACCORD Ann Intern Med. 2009;150(11):803-808. doi:10.7326/0003-4819-150-11-200906020-00008

Risk for Mr. Smith? UKPDS VADT ADVANCE ACCORD Ann Intern Med. 2009;150(11):803-808. doi:10.7326/0003-4819-150-11-200906020-00008

*Hypoglycemia rates were 2-fold higher for older patients (≥75 years) Rates of Estimated Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries With DM, 1999 to 2011 hypoglycemia hyperglycemia *More likely to be admitted with hypoglycemia than hyperglycemia in DMII *Hypoglycemia rates were 2-fold higher for older patients (≥75 years) JAMA Intern Med. 2014 Jul;174(7):1116-24. doi: 10.1001/jamainternmed.2014.1824.

Survival as a Function of HgbA1c in People with Type 2 DM Hazard Ratio (95% CI) HbA1c The Lancet, Volume 375, Issue 9713, 2010, 481 - 489

Metabolic Memory and Glycemic Legacy UKPDS and VADT Start of intensive therapy in VADT Start of intensive therapy in UKPDS 98 Drives risk of Complications Risk of complications continues despite glycemic control A1C (%) Bad Glycemic Legacy 76 SPEAKER NOTES: This figure is a hypothetical representation of the natural history of patients with T2DM in the VADT study. The upper dashed line represents the time course of HbA1c estimated by the average glucose profile in the UKPDS, based on the premise that duration of diabetes in VADT would be similar to that in UKPDS. The lower dashed line represents the ideal time course of glycemic control (early and sustained at time of diagnosis). The solid line to the right represents the time course of HbA1c in the VADT (mean time between diagnosis and start of intensive treatment in VADT = 11.4 years). Intensive therapy implemented in VADT resulted in a rapid lowering of plasma glucose levels close to the ideal target. However, this time course is far from the ideal (ie, the achievement and maintenance of near-normal glycemia from the time of diagnosis). The difference between the ideal and the actual time course of glycemic control represents a time period that may have had some impact on the effect of subsequent tight glycemic control (ie, the glycemic legacy). REFERENCE: 1. Del Prato S. Diabetalogia. 2009;52:1219-1226. Ideal course = early and sustained glycemic control 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time Since Diagnosis (years) Del Prato S. Diabetalogia. 2009;52:1219-1226.

Diabetes in Older Adults: A Consensus Report Pt characteristics Rationale A1C goal* Healthy Longer remaining life expectancy < 7.5 Multiple co-existing chronic illnesses or 2+ iADL impairments Intermediate remaining life expectancy, high tx burden, hypoglycemia vulnerability, fall risk <8 LTC, end stage of chronic illnesses, or 2+ ADL impairments Limited remaining life expectancy makes benefit uncertain <8.5 *Reasonable goal JAGS 2012: Kirkman et al. Diabetes in older adults: a consensus report.

Conclusions TREAT for SUCCESS not for FAILURE Choose your targets and go for goal with the window of opportunity Titration does not work in clinical practice ( Titration is a tardy task) Overcome Clinical Inertia Combine drugs initially depending on goal and use half maximal dosages in combinations We now have the tools to target the risk factors for CVD in Diabetes and the Metabolic Syndrome There is still a large proportion of morbidity and mortality and choose therapy and goal based upon risk stratification TREAT for SUCCESS not for FAILURE